Blood and lymphatic vessels form a versatile transport network and provide inductive signals to regulate tissue-specific functions. Blood vessels in bone regulate osteogenesis and hematopoiesis, but current dogma suggests that bone lacks lymphatic vessels. Here, by combining high-resolution light-sheet imaging and cell-specific mouse genetics, we demonstrate presence of lymphatic vessels in mouse and human bones. We find that lymphatic vessels in bone expand during genotoxic stress. VEGF-C/VEGFR-3 signaling and genotoxic stress-induced IL6 drive lymphangiogenesis in bones. During lymphangiogenesis, secretion of CXCL12 from proliferating lymphatic endothelial cells is critical for hematopoietic and bone regeneration. Moreover, lymphangiocrine CXCL12 triggers expansion of mature Myh11⁺ CXCR4⁺ pericytes, which differentiate into bone cells and contribute to bone and hematopoietic regeneration. In aged animals, such expansion of lymphatic vessels and Myh11-positive cells in response to genotoxic stress is impaired. These data suggest lymphangiogenesis as a therapeutic avenue to stimulate hematopoietic and bone regeneration.

血管和淋巴管形成一个多功能的运输网络，并提供感应信号来调节组织特异性功能。骨骼中的血管调节成骨和造血，但目前的教条表明骨骼缺乏淋巴管。在这里，通过结合高分辨率光片成像和细胞特异性小鼠遗传学，我们证明了小鼠和人类骨骼中存在淋巴管。我们发现骨骼中的淋巴管在基因毒性应激期间扩张。 VEGF-C/VEGFR-3 信号传导和基因毒性应激诱导的 IL6 驱动骨骼中的淋巴管生成。在淋巴管生成过程中，增殖的淋巴内皮细胞分泌 CXCL12 对于造血和骨再生至关重要。此外，淋巴管分泌因子 CXCL12 触发成熟 Myh11 ⁺ CXCR4 ⁺周细胞的扩张，这些周细胞分化为骨细胞并有助于骨和造血再生。在老年动物中，淋巴管和 Myh11 阳性细胞响应基因毒性应激的扩张受到损害。这些数据表明淋巴管生成是刺激造血和骨再生的治疗途径。